FoxO6, a member of the Forkhead box O (FOXO) transcription factor family, is involved in various physiological and pathological processes. It mediates insulin action on target genes, integrating insulin signaling with glucose and lipid metabolism. FoxO6 also plays roles in apoptosis, oxidative stress, autophagy, cell cycle control, and inflammation, and is associated with diseases like insulin resistance, dietary obesity, type 2 diabetes, and neurodegeneration [2,3]. Genetic models, such as gene knockout mice, have been crucial in studying FoxO6's functions.

In aged rats fed a high-fat diet, FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia. FoxO6-Tg mice showed increased lipid accumulation in the liver, while FoxO6-KO mice had attenuated lipogenesis gene expression, less hepatic lipid accumulation, and mitigated hyperlipidemia. Elevated glucose-induced FoxO6 upregulation led to increased ApoC3 expression and cellular triglyceride-mediated lipid accumulation [5]. In skin photoaging, UVB-irradiated hairless mice had suppressed FoxO6, increased inflammation, and decreased antioxidant levels. PAR2 inhibition or deletion in these mice increased FoxO6 levels, reducing inflammation and oxidative stress [1]. In melanogenesis, FoxO6 knockdown in B16F10 cells increased melanin content, while its activation reduced melanin content by inducing antioxidant genes in UVB-exposed cells [4]. In mouse cortical development, FoxO6 -/+ and FoxO6 -/- mice showed altered cortical development with migrating neurons halted in the intermediate zone, and FoxO6 affected Plxna4-mediated neuronal migration [6].

In conclusion, FoxO6 is a key regulator in multiple biological processes. Model-based research, especially using KO mouse models, has revealed its role in diseases such as metabolic disorders, skin aging, and neurodegeneration-related processes. Understanding FoxO6's functions provides potential therapeutic targets for these diseases.

References:

1. Bang, EunJin, Kim, Dae Hyun, Chung, Hae Young. 2021. Protease-activated receptor 2 induces ROS-mediated inflammation through Akt-mediated NF-κB and FoxO6 modulation during skin photoaging. In Redox biology, 44, 102022. doi:10.1016/j.redox.2021.102022. https://pubmed.ncbi.nlm.nih.gov/34082382/

2. Lee, Sojin, Dong, H Henry. 2017. FoxO integration of insulin signaling with glucose and lipid metabolism. In The Journal of endocrinology, 233, R67-R79. doi:10.1530/JOE-17-0002. https://pubmed.ncbi.nlm.nih.gov/28213398/

3. Li, Songzhe, Ye, Ting, Hou, Zhitao, Hao, Zhihua, Chen, Jing. 2025. FOXO6: A unique transcription factor in disease regulation and therapeutic potential. In Pharmacological research, 214, 107691. doi:10.1016/j.phrs.2025.107691. https://pubmed.ncbi.nlm.nih.gov/40058512/

4. Moon, Kyoung Mi, Lee, Bonggi, Kim, Dae Hyun, Chung, Hae Young. 2020. FoxO6 inhibits melanogenesis partly by elevating intracellular antioxidant capacity. In Redox biology, 36, 101624. doi:10.1016/j.redox.2020.101624. https://pubmed.ncbi.nlm.nih.gov/32863230/

5. Kim, Dae Hyun, Lee, Seulah, Noh, Sang Gyun, Lee, Jaewon, Chung, Hae Young. 2024. FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet. In Aging, 16, 4095-4115. doi:10.18632/aging.205610. https://pubmed.ncbi.nlm.nih.gov/38441531/

6. Paap, Ricardo H, Oosterbroek, Saskia, Wagemans, Cindy M R J, Hoekman, Marco F M, Smidt, Marten P. 2016. FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development. In Proceedings of the National Academy of Sciences of the United States of America, 113, E7087-E7096. doi:10.1073/pnas.1609111113. https://pubmed.ncbi.nlm.nih.gov/27791111/